It is generally recognized that the following four factors compromise the oral bioavailability of drugs from solid dosage forms: I) low solubility and/or dissolution rate in the gastrointestinal (GI) tract, ii) low membrane permeability, iii) interaction with components of the GI tract leading to complex formation, and iv) metabolism in the liver, the GI lumen or in the GI mucosa (either membrane or cytosol related). Drugs having a dissolution—limited oral absorption might benefit from a reduction in particle size, as well as from an increase in saturation solubility, as pointed out in the following equation which is a modification of the well known Noyes-Whitney relation:
            ⅆ      M              ⅆ      t        =            AD      ⁡              (                              C            s                    -                      C            t                          )              h  where dM/dt is the dissolution rate, A the specific surface area of the drug particle, D the diffusion coëfficient, h the diffusion layer thickness, Cs the saturation solubility, and Ct the drug concentration at time t. Both principles form the rationale for the use of solid dispersions, a possible pharmaceutical strategy that can result in increased solubility and dissolution rate. The term refers to a dispersion of one or more active ingredients in an inert and hydrophilic carrier or matrix in the solid state, prepared by melting (fusion) or solvent method. The presence of the carrier not only prevents aggregation/agglomeration of individual drug particles exhibiting a high solid-liquid surface tension, it also creates a micro-environment in which the drug solubility is high. Solid dispersions are physico-chemically classified as eutectics, solid solutions, glass solutions and suspensions, amorphous precipitates in a glassy or crystalline carrier, complex formations, and/or a combination of the different systems. Although the use of solid dispersions has been reported frequently in the pharmaceutical literature, very few marketed products rely on the solid dispersion strategy. The main reason for this discrepancy is the physical instability (aging effects) of these structures which ate often metastable. Phase separation, crystal growth or conversion from the amorphous (metastable) to the crystalline state during storage, inevitably results in decreased solubility and dissolution rate.
The presence of the carrier (often a polymer) is often adequate to prevent recrystallization. Recently, it was stated by Motsumoto and Zografi [1] that stabilization of amorphous indomethacin in PVP and PVPVA64 dispersions was mainly the consequence of drug-polymer interactions, while Van den Mooter et al. [2] clearly showed that the antiplasticizing effect of those polymers in dispersions with ketoconazole was the only stabilizing factor. A proper choice of polymer will increase the glass transition temperature (Tg) of the binary system in a way that the molecular mobility becomes extremely low at room temperature hence leading to acceptable physical stability. This increase in Tg is only occurring when the drug is completely dissolved (dispersed at molecular level) in the polymer with the absence of free glassy or crystalline drug.
Besides the homogeneous dispersion (at molecular level) of the drug in the polymer matrix, we hypothesize that the intrinsic dissolution properties of the polymer are also important. The polymer should dissolve slowly enough so that the drug is able to go into solution together with the polymer. Indeed in this way the polymer can create a microenvironment where the drug solubility is favored. This is of course only valid if a polymer is selected that will increase the solubility of the drug in the aqueous environment. The microenvironment is not adequate if the polymer dissolves too fast. On the other hand too slow a dissolution rate of the polymer will result in too slow a release of the drug. Taking the above mentioned considerations into account we selected several carriers (polymers) to prepare solid dispersions showing physical stability and improved dissolution properties. In order to challenge the selected polymers, itraconazole was chosen as a model drug. It is known that this drug (classified as a class II drug in the BCS) [3] has an extremely low aqueous solubility and dissolution rate The aim of the present invention describes the dissolution properties (pharmaceutical performance) and physical properties of solid dispersions of itraconazole and a fast (PVPVA64), a slow (eudragit E100) dissolving polymer, and combinations thereof prepared by hot-stage extrusion.